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Fertility Preservation in (Breast) Cancer Patients: Is it Safe?

Leuven Cancer Institute, University Hospital Gasthuisberg, Leuven, Belgium

To the Editor:

We welcome the American Society of Clinical Oncology (ASCO) guidelines on fertility preservation during cancer therapy.¹ This issue becomes even more important because there is a clear increase in the mean age of first gestation, as also reported by Flanders et al.² An important question for the physician and the patient, especially for those patients being treated for a hormone-sensitive cancer such as hormone-positive breast cancer, is the safety of fertility preservation. ASCO's current recommendations correctly state that "there is insufficient evidence regarding the safety and effectiveness of gonadotropin-releasing hormone (GnRH) analogs in women with hormone-sensitive tumors. Women interested in ovarian suppression for this purpose are encouraged to participate in clinical trials." Unfortunately, current clinical trials will not answer the safety issue of fertility preservation in young women receiving chemotherapy for a nonmetastatic hormone-sensitive breast cancer. Moreover, a very large international trial, the Tamoxifen and Exemestane Trial (TEXT), already assumes that the combination of GnRH-analogs with chemotherapy is safe.

Women of childbearing age with early-stage breast cancer are at higher risk for relapse than older women and are therefore more likely to receive adjuvant chemotherapy. In such cases, tamoxifen is given after completion of chemotherapy because combining both therapies yields inferior results. This has been clearly demonstrated in a large phase III trial³ that showed that overall survival was significantly shorter when tamoxifen was given concomitantly with chemotherapy compared with the sequential administration. The combination of two powerful anticancer strategies is acceptable if synergism or additive effects occur, but sometimes the two strategies might counteract each other. Our experience with the combination of tamoxifen and chemotherapy suggests that hormone therapy could cause growth arrest in tumor cells and render these cells less sensitive to chemotherapy.

The situation with combined ovarian suppression and chemotherapy might be different but there are no good data, and counteracting mechanisms cannot be excluded until this is properly investigated. The TEXT trial already considers the combination of chemotherapy together with ovarian suppression as a standard. Premenopausal patients are randomly assigned to ovarian suppression plus tamoxifen versus ovarian suppression plus exemestane. In patients for whom additional chemotherapy is advised, the GnRH analog therapy needs to be given before the start of chemotherapy. The safety of this approach only comes from indirect evidence. Many studies show that amenorrhea after chemotherapy improves outcome, and this argument is used to defend the design of the TEXT trial. However in these cases, amenorrhoea generally occurred only after several cycles of chemotherapy. Tumor cells have thus been exposed for a few months to chemotherapy while they were still "activated" by high doses of estrogen. Chemotherapy could be theoretically more active in this case compared with the situation where hormonal stimulation of tumor cells has already stopped before the start of chemotherapy. Another indirect argument comes from combinations of tamoxifen and ovarian suppression/ablation. Results from the Zoladex in Premenopausal Patients (ZIPP)⁴ study showed that the addition of 2 years of the luteinizing hormone-releasing hormone (LHRH) –agonist goserelin to standard tamoxifen is more effective than tamoxifen alone. In metastatic breast cancer, the combination of LHRH analogs and tamoxifen was superior to tamoxifen alone in terms of overall survival.⁵ In contrast with these findings, ovarian suppression/ablation did not add to adjuvant chemotherapy followed by tamoxifen or tamoxifen alone in the international Adjuvant Breast Cancer (ABC) trial of 2,144 patients with early breast cancer.⁶ The ongoing global Suppression of Ovarian Function Trial (SOFT) will provide further data on this issue. In contrast with the TEXT trial, SOFT requests ovarian suppression only after the end of chemotherapy. Anyhow, the results from combining LHRH analogs and tamoxifen are not uniform. Moreover, interactions between these two treatment modalities cannot be extrapolated to the combination of chemotherapy and LHRH analogs.

Current trials by the Southwest Oncology Group and the Anglo-Celtic Breast Group (OPTION) investigated the efficacy of GnRH in preserving fertility in hormone receptor–negative breast cancer, but avoided the important question of hormone-sensitive breast cancer. Fortunately, the OPTION trial has recently amended their protocol to include premenopausal patients with hormone-sensitive breast cancer, but the question is whether this subgroup will be sufficiently powered to provide answers.

In conclusion, we believe that currently ongoing trials (except maybe the recently amended OPTION trial) will only answer the question whether GnRH analogs preserve fertility/premature menopause following the use of chemotherapy but not to the question regarding its safety (antitumor effect) in case of hormone-sensitive breast cancer. We believe that the TEXT trial, unlike the Albain et al trial,³ misses the great opportunity to tackle the safety issue of concomitant or sequential LHRH and chemotherapy administration. In a third arm or in a 2 x 2 factorial design, GnRH-analog could be given after completion of chemotherapy.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24 : 2917 -2931, 2006[Abstract/Free Full Text]

2. Cammu H, Martens G, De Coen K, et al: Perinatal activities in Flanders [Flemish]. Brussels, Belgium, vzw Studiecentrum voor Perinatale Epidemiologie, 2004

3. Albain K, Barlow W, O'Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). Presented at the 27th San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 37)

4. Baum M, Hackshaw A, Houghton J, et al: Adjuvant goserelin in pre-menopausal patients with early breast cancer. Results from the ZIPP study. Eur J Cancer 42 : 895 -904, 2006[CrossRef][Medline]

5. Klijn JGM, Blamey RW, Boccardo F, et al: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: A meta-analysis of four randomized trials. J Clin Oncol 19 : 343 -353, 2001[Abstract/Free Full Text]

6. Yarnold JR, Bliss JM, Earl H, et al: Ovarian ablation in pre-menopausal women with early breast cancer prescribed 5 years tamoxifen or tamoxifen plus chemotherapy: Results from the UK NCRI adjuvant breast cancer interantional trial of 2144 patients. J Clin Oncol 22 : 11s , 2004 (suppl; abstr 535)

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wildiers, H. Articles by Paridaens, R. Search for Related Content PubMed PubMed Citation Articles by Wildiers, H. Articles by Paridaens, R. Social Bookmarking                            What's this?